Use of fluoroalkoxysulfur fluorides in fluorinations

ABSTRACT

Fluoroalkoxysulfur fluorides of the formula ##STR1## wherein R is H, CH 3 , CF 3 , or C 2  F 5 , and n is 1 or 2, used as fluorinating agents to replace OH groups in organic molecules with F and halocarbon solutions of lithium fluoroalkoxides.

CROSS-REFERENCE TO RELATED APPLICATION

This is a divisional application of copending application bearing U.S.Ser. No. 148,209, filed on May 9, 1980, now U.S. Pat. No. 4,311,651.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to fluoroalkoxysulfur fluorides used asfluorinating agents to replace hydroxyl groups with fluorine in organicmolecules. Also of concern are solutions of the intermediate lithiumfluoroalkoxides in halocarbon solvents.

2. State of the Art

Baum, in J. Am. Chem. Soc., 91, 4594 (1969), describes the preparationof 2-fluoro-2,2-dinitroethoxysulfur trifluoride by reaction of2-fluoro-2,2-dinitroethanol with sulfur tetrafluoride. This compoundwould not have utility as a fluorinating agent because its two nitrogroups would make it explosive. Furthermore, isolation of fluorinatedreaction products from a reaction mixture containing this compound wouldbe complicated by its low volatility and that of its expectedby-products.

Darragh et al, in J. Chem. Soc., Dalton Trans., 1975, 218,, describe thepreparation of several aryloxysulfur trifluorides and diaryloxysulfurdifluorides by the reaction of aryl silyl ethers and sulfurtetrafluoride. These compounds would not have fluorinating utilitybecause they are generally unstable. In addition, the isolation offluorinated reaction products, if formed, from reaction mixturescontaining the aryloxysulfur trifluorides, would be complicated by thelow volatility of the aryloxysulfur trifluorides and their expectedby-products. The authors state that they made unsuccessful attempts toprepare alkoxy derivatives of sulfur (IV) fluorides.

Among the most useful known fluorinating agents are thedialkylaminosulfur trifluorides (DAST) of U.S. Pat. No. 3,914,265 andthe bis(dialkylamino)sulfur difluorides of U.S. Pat. No. 3,888,924. Thefluoroalkoxysulfur fluorides of this invention offer certain advantagesover these known fluorinating agents because they are safer to use atelevated temperatures, they are more soluble in non-polar solvents, andaqueous work-up can be avoided because the by-products are volatile.

SUMMARY OF THE INVENTION

The compounds used in the fluorination process of this invention arefluoroalkoxysulfur fluorides of the formula: ##STR2## wherein R isselected from H, CH₃, CF₃ and C₂ F₅, and n is 1 or 2.

The compounds are prepared by reacting lithium salts of fluoroalcoholswith sulfur tetrafluoride according to the sequence: ##STR3## wherein Ris as defined above.

The fluoroalkoxysulfur fluorides are useful as fluorinating agents forreplacing hydroxyl groups of organic compounds with fluorine atoms, andcan be used in the preparation of fluorine-containing pharmaceuticals.Typical fluorination reactions involve contacting the fluoroalkoxysulfurfluoride with a solution of the organic hydroxyl compound in a volatile,inert solvent and then isolating the product in nearly pure form byevaporating the solvent.

Another aspect of this invention concerns novel solutions of theintermediate lithium fluoroalkoxides in halocarbon solvent. Suchsolutions have not been reported previously and the fact that they canbe made is interesting in view of the fact that alkali metal alkoxidesare generally insoluble in nonpolar solvents.

DETAILS OF THE INVENTION

Preparation of compounds used in the process of this invention isconducted by adding a solution of the lithium salt in an inert solventto a solution of sulfur tetrafluoride in the same or different inertsolvent. Suitable inert solvents are those which are liquid at thereaction temperature and include halogenated hydrocarbons, such asCFCl₃, CH₂ Cl₂ and CHCl₃, and ethers such as dibutyl ether, diethylether, and 1,3-dimethoxybenzene. Reaction temperatures can vary betweenabout -20° and -100° C.; the preferred range for best yield is about-40° to -80° C. Pressure is not critical, but atmospheric pressure ispreferred for convenience.

The molar ratio of lithium salt to sulfur tetrafluoride will usuallyvary from about 3:1 to 1:10, respectively. Such ratios, however, are nota necessity. In general, an excess of the lithium salt favors theproduction of the bis(alkoxy)sulfur difluoride, (n=2), and an excess ofsulfur tetrafluoride favors the production of the mono(alkoxy)sulfurtrifluoride, (n=1), although in many cases, both products are formed atthe same time. The products are isolated from the reaction mixture bydistillation, either at atmospheric pressure or reduced pressure.

Representative hydroxyl compounds which can be fluorinated by theprocess of this invention include monofunctional and polyfunctionalaliphatic primary, secondary, and tertiary alcohols, all of which cancontain other substituents. Examples are benzyl alcohol, phenylethylalcohol, stearyl alcohol, cholesterol, polyvinyl alcohol, and morecomplex hydroxyl compounds such as cephalosporins (e.g., benzhydryl3-hydroxymethyl-7-(2-thienylacetamido)-3-cephem-4-carboxylate-1-oxide)and benzodiazepines (e.g., temazepam).

The following Examples illustrate the invention and the preparationsillustrate the making of lithium salt intermediates. Temperatures are indegrees Centigrade.

PREPARATION A Lithium 1,1,1,3,3,3-Hexafluoroisopropoxide

    (CF.sub.3).sub.2 CHOH+BuLi→(CF.sub.3).sub.2 CHOLi+BuH

A stirred mixture of 168 g (1 mol) of 1,1,1,3,3,3-hexafluoroisopropanoland 300 ml of hexane was cooled to 10°, and one mole of butyllithium inhexane (1.6 M) was added dropwise, keeping the temperature between 10°and 20°. The solid that formed was collected on a filter (undernitrogen) and washed with hexane to give 128.2 g of white powder. Asecond crop of 23.63 g was obtained by concentrating the hexanefiltrate. In total, 151.83 g (87%) of lithium1,1,1,3,3,3-hexafluoroisopropoxide was obtained as a white, hygroscopicpowder, mp 144° (d); ¹ H NMR (CFCl₃) δ 4.34 ppm (septet, J=5 Hz); ¹⁹ FNMR (CDCl₃) δ -79.0 ppm (d, J=5 Hz).

Anal. Calcd. for c₃ HF₆ LiO: F, 65.52. Found: F, 65.61.

PREPARATION B Lithium 2,2,2-Trifluoro-1,1-bis(trifluoromethyl)ethoxide

    (CF.sub.3).sub.3 COH+BuLi→(CF.sub.3).sub.2 COLi+BuH

A stirred mixture of 11.8 g (0.05 mol) of2,2,2-trifluoro-1,1-bis(trifluoromethyl)ethanol in 40 ml of hexane wascooled to -10°, and 0.05 mol of butyllithium in hexane (1.6 M) was addeddropwise. The reaction mixture was warmed to 25°, and the solidprecipitate was collected on a filter and dried under a stream of drynitrogen to give 10.69 g (88% of lithium2,2,2-trifluoro-1,1-bis(trifluoromethyl)ethoxide, mp 139° to 141°(dec.).

Anal. Calcd. for C₄ F₉ OLi: F, 70.66. Found: F, 70.27.

EXAMPLE 1 2,2,2-Trifluoro-1-(trifluoromethyl)ethoxysulfur Trifluoride

    (CF.sub.3).sub.2 CHOLi+SF.sub.4 →(CF.sub.3).sub.2 CHOSF.sub.3 +LiF

A solution of 66.1 g (0.38 mol) of lithium1,1,1,3,3,3-hexafluoroisopropoxide in 200 ml of dibutyl ether was addeddropwise to a solution of 30 ml (measured at -78°, 0.54 mol) of SF₄ in100 ml of dibutyl ether cooled to -70°. The reaction mixture was warmedto room temperature, and the volatile material was distilled out atreduced pressure into a trap cooled to -78°. The distillate wasredistilled at atmospheric pressure in a spinning band still to give26.36 g (27%) of 2,2,2-trifluoro-1-(trifluoromethyl)ethoxysulfurtrifluoride as a colorless, fuming liquid: bp 57° to 59°; ¹⁹ F NMR(CFCl₃) δ -74.1 ppm (d, J=5 Hz,6F), +29.9 ppm (t, J=73 Hz,1F) and +77.9ppm (d, J=73 Hz,2F).

Anal. Calcd. for C₃ HF₉ OS: F, 66.77; S, 12.52. Found: F, 66.57; S,12.12.

EXAMPLE 2 Bis[2,2,2-trifluoro-1-(trifluoromethyl)ethoxy]sulfurDifluoride

    ______________________________________                                         ##STR4##                                                                 

A solution of 66.1 g (0.38 mol) of lithium1,1,1,3,3,3-hexafluoroisopropoxide in 100 ml of CFCl₃ was added dropwiseto a solution of 30 ml (measured at -78°, 0.54 mol) of sulfurtetrafluoride in 100 ml of CFCl₃ cooled to -70°. The reaction mixturewas warmed to room temperature, filtered to remove the precipitatedsolid, and then distilled to give 18.14 g (24%) ofbis[2,2,2-trifluoro-1-(trifluoromethyl)ethoxy]sulfur difluoride as acolorless liquid, bp 37° to 39° (23 mm); ¹ H NMR (CFCl₃ 5.58 ppm (m); ¹⁹F NMR (CFCl₃) δ -73.9 ppm (d, J=5 Hz, 12F) and +63.1 ppm (2F).

Anal. Calcd. for C₆ H₂ F₁₂ O₂ S: F, 65.82; S, 7.94. Found: F, 66.03; S,8.33.

EXAMPLE 3 2,2,2-Trifluoro-1-(trifluoromethyl)ethoxysulfur Trifluoride

    (CF.sub.3).sub.2 CHOLi+SF.sub.4 →(CF.sub.3).sub.2 CHOSF.sub.3 +LiF

A solution of 33.0 g (0.16 mol) of lithium1,1,1,3,3,3-hexafluoroisopropoxide in 100 ml of 1,3-dimethoxybenzene wasadded dropwise to a solution of 30 ml (measured at -78°, 0.54 mol) ofsulfur tetrafluoride in 100 ml of 1,3-dimethoxybenzene cooled to -50°.The reaction mixture was warmed to 25°, and the volatile material wasdistilled out at reduced pressure into a trap cooled to -78°. Thedistillate was redistilled through a spinning band still, with carebeing taken to keep the pot temperature below 70°, to give 26.4 g (54%)of 2,2,2-trifluoro-1-(trifluoromethyl)ethoxysulfur as a colorless,fuming liquid, bp 57° to 59°; and 4.5 g ofbis[2,2,2-trifluoro-1-(trifluoromethyl)ethoxy]sulfur difluoride as acolorless, fuming liquid, bp 45° to 50° (50 mm).

EXAMPLE 4 Bis[2,2,2-trifluoro-1-(trifluoromethyl)ethoxy]sulfurDifluoride

    2(CF.sub.3).sub.2 CHOLi+SF.sub.4 →[(CF.sub.3).sub.2 CHO].sub.2 SF.sub.2 +2LiF

A solution of 33.0 g (0.16 mol) of lithium1,1,1,3,3,3-hexafluoroisopropoxide in 100 ml of 1,3-dimethoxybenzene wasadded dropwise to a solution of 4.5 ml (measured at -78°, 0.08 mol) ofsulfur tetrafluoride in 50 ml of 1,3-dimethoxybenzene cooled to -50°.The reaction mixture was warmed to 25°, and the volatile material wasdistilled out at reduced pressure into a trap cooled to -78°. Thedistillate was redistilled to give 8.78 g (30%) ofbis[2,2,2-trifluoro-1-(trifluoromethyl)ethoxy]sulfur difluoride as acolorless liquid, bp 42° to 44° (40 mm).

EXAMPLE 5 2,2,2-Trifluoro-1,1-bis(trifluoromethyl)ethoxysulfurTrifluoride andBis[2,2,2-trifluoro-1,1-bis(trifluoromethyl)ethoxy]sulfur Difluoride##STR5##

A solution of 10.5 g (0.043 mol) of lithium2,2,2-trifluoro-1,1-bis(trifluoromethyl)ethoxide in 60 ml of dibutylether was added dropwise to a solution of 8 ml (measured at -78° C.,0.15 mol) of sulfur tetrafluoride in 50 ml of dibutyl ether cooled to-70° C. The reaction mixture was warmed to 25° C., and the volatileswere distilled out at reduced pressure and condensed in a cold trap at-78° C. The condensate was fractionated to give (A) 2.91 g of2,2,2-trifluoro-1,1-bis(trifluoromethyl)ethoxysulfur trifluoride as acolorless liquid: bp 56° to 60°; ¹⁹ F NMR (CCl₃ F) δ -71.4 ppm (q, J=3.0Hz,9F) and 44.0 ppm (broad, 3F) and (B) 3.60 g ofbis[2,2,2-trifluoro-1,1-(trifluoromethyl)ethoxy]sulfur difluoride as acolorless liquid: bp 35° to 37° C. (20 mm); ¹⁹ F NMR (CCl₃ F) δ -71.7ppm (t, J=1.5 Hz, 18F) and +32.1 ppm (broad, 2F).

EXAMPLE 6 Fluorination of Temazepam with (CF₃)₂ CHOSF₃ ##STR6##

A solution of 5.12 g (0.02 mol) of2,2,2-trifluoro-1-(trifluoromethyl)ethoxysulfur trifluoride in 25 ml ofmethylene chloride was cooled to -70°, and a solution of 3.0 g (0.01mol) of temazepam in 10 ml of methylene chloride was added dropwise. Thereaction mixture was warmed to room temperature, and stirred for 1 hr.Sodium fluoride, 1 g, was added, and the mixture was stirred for 10 min,filtered, and then evaporated to dryness under reduced pressure. Theresidue was recrystallized from ethanol to give 2.48 g (82%) of7-chloro-3-fluoro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one(3-fluorodiazepam)as a white crystalline solid: mp 142° to 144°. The latter compound is atranquilizer as shown in U.S. Pat. No. 4,120,856.

EXAMPLE 7 Fluorination of 4-Nitrobenzyl Alcohol With (CF₃)₂ CHOSF₃##STR7##

A solution of 0.77 g (5 mmol) of 4-nitrobenzyl alcohol in 15 ml ofmethylene chloride was added dropwise over a period of 10 min to astirred solution of 2.0 g (7.8 mmol) of2,2,2-trifluoro-1-(trifluoromethyl)ethoxysulfur trifluoride in 5 ml ofmethylene chloride cooled to 10°. The reaction mixture was warmed toroom temperature and then evaporated to dryness under reduced pressure.The residue was recrystallized from pentane to give 0.59 g (76%) of4-nitrobenzyl fluoride as colorless needles: mp 33° to 34°.Recrystallization from pentane raised to melting point to 36° to 37°.

EXAMPLE 8 Fluorination of 4-Nitrobenzyl Alcohol With [(CF₃)₂ CHO]₂ SF₂##STR8##

A solution of 770 mg (5 mmol) of 4-nitrobenzyl alcohol in 15 ml ofmethylene chloride was added dropwise to a stirred solution of 3.0 g(7.5 mmol) of bis[2,2,2-trifluoro-1-(trifluoromethyl)ethoxy]sulfurdifluoride in 5 ml of methylene chloride at 25°. The reaction mixturewas stirred for 18 hrs, and then evaporated to dryness under reducedpressure. The residue was recrystallized from pentane to give 490 mg(63%) of 4-nitrobenzyl fluoride as colorless needles, mp 33° to 34°. Asecond recrystallization raised the melting point to 36° to 37°. The4-nitrobenzyl fluoride is a known compound useful as a chemicalintermediate.

I claim:
 1. A process for replacing a hydroxyl group of a monofunctionalor polyfunctional aliphatic primary, secondary or tertiary alcohol withfluorine, comprising reacting said alcohol with a fluoroalkoxysulfurfluoride of the formula ##STR9## wherein R is selected from H, CH₃, CF₃and C₂ F₅, and n is 1 or
 2. 2. A process according to claim 1 wherein Ris H.
 3. A process according to claim 1 wherein R is CH₃.
 4. A processaccording to claim 1 wherein R is CF₃.
 5. A process according to claim 1wherein R is C₂ F₅.
 6. A process according to any one of claims 1 to 5wherein n is
 1. 7. A process according to any one of claims 1 to 5wheein n is
 2. 8. A solution of lithium fluoroalkoxide of the formula##STR10## wherein R is selected from H, CH₃, CF₃, and C₂ F₅ in anon-polar halocarbon solvent.